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Here, we examine the effect of vesicular release of the anxiolytic antipsychotic drug cyamemazine on electrically evoked striatal dopamine responses with fast scan cyclic voltammetry. Remarkably, in the presence of nanomolar extracellular cyamemazine, vesicular cyamemazine release in the brain slice can increase dopamine responses 30-fold. Kinetic analysis and multiple stimulation experiments show that this occurs by inducing delayed emptying of the releasable dopamine pool. Also consistent with increased dopamine release, an antagonist (dihydro-\u03b2-erythroidine) implicates nicotinic acetylcholine receptors, which can directly cause dopamine release, in the vesicular cyamemazine effect. Therefore, vesicular release of cyamemazine can dramatically enhance dopaminergic synaptic transmission, possibly by recruiting an excitatory cholinergic input to induce an extra phase of release. More generally, this study suggests that synaptic drug release following vesicular accumulation by acidic trapping can expand psychiatric drug pharmacodynamics.<\/jats:p>","DOI":"10.1093\/schbul\/sbz085","type":"journal-article","created":{"date-parts":[[2019,7,8]],"date-time":"2019-07-08T03:06:23Z","timestamp":1562555183000},"page":"643-649","source":"Crossref","is-referenced-by-count":7,"title":["Vesicular Antipsychotic Drug Release Evokes an Extra Phase of Dopamine Transmission"],"prefix":"10.1093","volume":"46","author":[{"given":"Seth H","family":"Walters","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3319-1344","authenticated-orcid":false,"given":"Edwin S","family":"Levitan","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, 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